Microgels

ABSTRACT

A microgel is produced by a two-stage process wherein the monomers are first polymerized in the absence of solvent for a controlled period, and in a second stage solvent is added and polymerization is completed. The polymer is preferably a polyurethane formed from a polyalkylene glycol, a triol and a diisocyanate. The molecular weight is typically 100,000 to 200,000. The microgels form granules which may be compressed into solid form. Such solid forms containing an active agent, such as a protein, are useful as sustained delivery devices.

FIELD OF THE INVENTION

The present invention relates to a process for the production of amicrogel. The process enables the production of microgels in a simpleand economic manner. The invention also relates to microgels themselves,particularly when compressed or melted into a solid body.

BACKGROUND

Prior patent specification GB2090264 discloses a solution polymerisationprocess for the preparation of polymeric materials comprisingcross-linked particles which are capable of forming sols, that is tosay, a class of hydrogels which are referred to as microgels. Theprocess involves polymerising one or more monomers in a solvent havingparticular characteristics and terminating the polymerisation beforemacrogelation occurs.

Microgels may be defined as intramolecularly cross-linkedmacromolecules. In common with other cross-linked polymers, microgelshave a cross-linked structure and fixed surfaces. On the other hand,microgels may generally speaking be dissolved in certain solvents in thesame way as non-cross-linked linear or branched polymers of similarmolecular weight. In conventional cross-linked polymers, macrogelationoccurs such that an extensive three-dimensional network is set up, whichgenerally speaking resists dissolution in solvents. In microgels, thecross-linking structure exists predominantly within individual globularmolecules.

The special molecular structure of microgels and their ability to existas globular particles makes the microgel a promising material forpharmaceutical applications, such as carriers for controlled drugdelivery. Patent specifications GB2090264, GB2143733 and GB2230952disclose sustained release devices comprising an active ingredient and ahydrogel.

It is therefore foreseen that microgels may have a variety of potentialindustrial uses, and it would be desirable to provide an improvedproduction process capable of producing microgels in a simple efficientand economical manner. Originally, microgels had to be produced at highdilutions which favour intramolecular rather than intermolecularcross-linking. Patent specification GB2090264 exemplifies an improvedprocess for the production of microgels at higher concentrations insolvents having particular defined characteristics and under certainconditions which favour microgel formation. Generally speaking, themicrogels formed have good solubility in the solvents used in theproduction process, so that solid microgel granules are generallyobtained by precipitation of the microgel from solution by the additionof an organic liquid such as hexane, cyclohexane, petrol ether ormethanol. However, the addition of a further organic liquid to thesolvent used in the microgel production reaction means that the solventcannot be directly reused without costly procedures for recovering thesolvent from the mixture formed with the organic liquid. Furthermore,the microgel granule size or shape may not be suitable for direct use asa tabletting excipient, so that further processing such as grinding andsieving may be needed. These expedients are undesirable and detract fromthe industrial applicability of such microgel production processes.

It is an object of the present invention to mitigate thesedisadvantages.

SUMMARY OF THE INVENTION

One aspect of the present invention provides a process for theproduction of a microgel, which comprises

(i) in a first step conducting a polymferisation reaction bycross-linking at least one monomer in a reaction mixture substantiallyfree of solvent therefor; and

(ii) thereafter in a second step, dissolving the reaction mixture in asolvent and completing the polymerisation to produce a microgel.

Polymerisation may generally be taken to completion withoutmacrogelation occurring, and there is therefore usually no need toterminate polymerisation prior to completion (though this is notexcluded).

Another aspect of the present invention relates to the microgel polymer,particularly in granular form. The process of the present invention hasbeen found to provide microgels having higher molecular weights thanthose obtained by conducting the polymerisation in a solvent in theabsence of the solvent-free first polymerisation step.

A third aspect of the invention relates to a sustained release devicecomprising the microgel and having incorporated therein an active agentto be released. Advantageously, the device is in the form of a compressof microgel granules having the active agent dispersed therethrough. Onswelling in water the compress generally becomes microporous but retainsits integral structure.

Thus, it is surprisingly found according to the present invention thatthe use of a solvent-free first stage of the polymerisation enablesmicrogels to be produced which may be more easily separated fromsolution, for example by cooling to precipitate microgels of goodcrystallinity. In fact, the crystal structure of microgels producedaccording to the present process appears to be improved over thoseproduced by known processes. That good microgels may be producedemploying a process which is, at least in its initial stage,solvent-free is surprising. It has hitherto been assumed that the natureand presence of the solvent from the beginning of the polymerisation isessential in order to favour intramolecular cross-linking and to preventmacrogelation occurring. Furthermore, since the microgels of the presentinvention may be separated from the reaction solution without the needto add any further organic liquid, the possibility exists for reusingthe polymerisation solvent directly. Water-soluble or insolublemicrogels may be produced.

Polymerisation may also proceed at a faster rate using the solvent-freefirst step of the present invention, compared to conventional processeswithout this step. Thus, the speed of production of the microgels may beenhanced.

The polymerisation reaction of the present invention may be an additionpolymerisation, for example a cationic, anionic or free radicalpolymerisation, or a step-growth or condensation polymerisation. Thepolymerisable monomer may in particular be any of those monomersdisclosed in U.S. Pat. No. 5,863,996 filed on Jun. 7, 1995.

However, the present invention is advantageously applied to theproduction of polyurethane microgels. In this case, the monomer is adihydroxy or polyhydroxy compound, such as a polyalkylene oxide,particularly polyethylene oxide or polypropylene oxide. Generally, theratio of number average molecular weight to functionality is greaterthan 1,000. Polyethylene glycols of number average molecular weight3,000 to 10,000 are particularly preferred. Production ofwater-insoluble polyurethane microgels tends to be favoured by usingrelatively low amounts of polyethylene oxide and relatively high amountsof cross-linking agent. Water soluble microgels may be made in conversemanner.

Cross-linking may be carried out using a suitable cross-linking agentknown in the art, such as a diisocyanate or polyisocyanate, for examplea (cyclo)aliphatic, araliphatic or aromatic diisocyanate. Specificexamples include 2,4 and 2,6 toluene diisqcyanate; (cyclo)aliphaticdiisocyanates such as 1, 6 hexamethylene diisocyanate, isophoronediisocyanate, 4, 4'-dicyclohexylmethane diisocyanate, and(cyclo)hexylene 1, 2- and 1,4-diisocyanate; and araliphaticdiisocyanates such as 4,4'-diphenylmethane diisocyanate.

In order to provide a three-dimensional branched polyurethane structure,the polymerisation reaction preferably also includes a polyfunctionalcompound having active hydrogen atoms, such as an aromatic or aliphaticpolyol, for example an aliphatic triol such as 1,2,6 hexantriol.

A particularly preferred polyurethane is formed by polymerising amixture of a polyethylene glycol, an aliphatic triol, and a diisocyanatein a molar ratio 1:1-8:2-15.

The solvent for the second step may in principal be any suitablesolvent, such as those disclosed in GB2090264. Preferably, the solventwill have a moderate solubility for the microgel at ambient temperature,such as to allow the microgel to be precipitated directly from solutionwithout the addition of any other substance thereto which would affectthe ability of the solvent to be directly reused in a furtherpolymerisation reaction. Methyl ethyl ketone is a particularly preferredsolvent for the production of polyurethane microgels. Acetone anddiethyl ketone may also be employed. The solvent is employed in thesecond step of the polymerisation process, and is generally added suchas to dilute the reaction mixture from the first step to a concentrationin the range 2 to 30%, preferably 5 to 20% wt/volume.

The properties of the finished microgels are dependent upon the extentof polymerisation which occurs during the first step in the absence ofsolvent. Generally, the first step is carried out for a time which isinsufficient for macrogelation to occur and this is usually in the range1 to 60 minutes, preferably 5 to 30 minutes, and particularly 10 to 20minutes. Generally, the reaction to completion in the second step asindicated by the disappearance of cross-linking agent takes less than 24hours. Thus the first step may take from about 0.5 to 2.0% of the totalpolymerisation time. A polyurethane will generally be produced bypolymerisation at a temperature in the range 50 to 100° C.

Microgels of the present invention generally have higher weight averagemolecular weights (e.g. above 40,000, typically in the range 100,000 to200,000) than those prepared conventionally without the solvent-freefirst step.

The microgel particles of the present invention tend to flow well and beless sticky than conventional microgels, and be of good size uniformity.This may be due to differences in chemical structure arising from thesolvent-free first step. Polyethylene oxide-based microgels are believedto comprise a hydrophobic core (composed for example in the case of apolyurethane primarily of aromatic moieties and polyol) and hydrophilicloops or side chains extending therefrom formed of polyethylene oxide.In the microgels of the present invention the loops or chains may belonger due to some linear polymer formation prior to cross-linking.

The microgel is preferably separated from solution by cooling thereaction mixture to a temperature below the temperature it whichpolymerisation is carried out, and below the melting temperature of thecrystalline portion of the microgel. For an industrial process,deposition of the solid microgel is preferably brought about at atemperature of 10 to 25° C. i.e. substantially room temperature;although cooling below room temperature may be used if necessary.

The microgels of the present invention have a particularly high degreeof crystallinity, which may be in the range 40 to 70% determined asdescribed herein. Generally, the microgels crystallise in the form ofgranules comprising globular microgel particles whose size shows goodconsistency. Thus, the average granule size may be in the range 10 to1,000 microns determined as described herein. Generally, the microgelsare crystallised from solution in the form of granules having a sillegreater than 0.1 mm, particularly 1 to 5 mm. Such microgel granules havebeneficial compaction properties so as to be suitable for compressionmoulding. Generally speaking, the microgel granules produced by theproduction process may be used directly, without any need for furthertreatment such as grinding or sieving.

Thus, the microgel granules of the present invention are particularlysuited to the production of solid sustained release devices produced bycompression, optionally under the effect of heat. Generally, thesustained release device includes an active agent which is disperseduniformly throughout the microgel compress. The sustained release deviceis intended to be placed in a liquid into which the active agent is tobe released, such as water. The microgel itself may be either soluble orinsoluble in the liquid in which the active agent is to be released. Inthe case of insoluble microgels, the liquid may gain access to theactive agent through pores present in the microporous compress.

It is a surprising property of the microgels of the present inventionthat they are able to produce a compress which on swelling in water doesnot disintegrate but becomes microporous. Compression may be carried outat room temperature and heating is not generally required.

However, the microgels can generally be melted at temperatures of lessthan 100° C. without decomposition, and this allows moulded forms to beproduced.

The active agent may be a pharmaceutical, bacteriostat, viricide,insecticide, herbicide, larvicide, fungicide, algicide, nematicide,anthelmintic, topical or dermatological agent, anti-foulant for marinegrowth prevention, enzyme, preservative, surfactant, pigment,disinfectant, sterilising agent or any other agent for which sustainedrelease is desirable. It is a particular benefit that the microgelsustained release device of the present invention may be used to deliverhigh molecular weight active agents, such as biologically activemolecules, particularly proteins. Since proteins and many peptides havehigh molecular weight and hydrophilicity, it has hitherto been difficultto find materials which can regulate the release of these substances.Although hydrogels have special potential for the release of proteinsdue to their relatively high permeability, hydrophilic nature andbiocompatability, introducing a protein into a hydrogel matrix hashitherto proved to be difficult. Prior methods have includedpolymerisatiorn of the hydrogel in the presence of the protein orpeptide, or loading the protein or peptide into the hydrogel by swellingthe hydrogel in an aqueous solution thereof and subsequently dryingagain. However, both these methods have disadvantages and may lead totoxic reaction products or a denatured protein. The microgels of thepresent invention allow production of a hydrogel matrix by compaction ofmicrogel granules admixed with the active agent at room temperature inthe dry state. This minimises possible degradation or contamination ofthe protein or peptide. Previously compaction of microgels generallyrequired heating.

In particular, the protein or peptide may be an antibody, an enzyme or ahormone. A microporous sustained release device may also deliver aliving micro-organism, such as a bacterium (for example lactobacillus)or a parasitic organism, such as those used to kill fungi or mosquitolarvae.

Water-soluble microgels may be used to deliver such biologically activematerials. They may also be used to aid solubility of an insoluble orsparingly soluble active agent.

The compressed or moulded microgel may be in any suitable solid form,such as a tablet or ball, cylinder, disc or block. The microgel solidform may be coated with a coating which is soluble or insoluble in theliquid into which the active agent is to be released. In the case of aninsoluble coating, a suitable aperture or apertures will be provided toallow ingress of liquid and release of active agent.

BRIEF DESCRIPTION OF DRAWINGS

FIG. 1 shows the distribution of particle sizes of microgel granules forthe sample x2.5-5-1.

FIG. 2 shows the release of bovine serum albumin (BSA) from a tablet ofmicrogel made by direct compression.

FIG. 3 shows the release of polyvinyl pyrrolidine (PVDP) and caffeinefrom a tablet of microgel made by direct compression.

FIG. 4 shows the release of caffeine from tablets made by melting andcompressing microgel samples x4-5-3, x3-5-3 and x2.5-5-3.

DETAILED DESCRIPTION OF PREFERRED EMBODIMENTS

Embodiments of the invention will now be described by way of exampleonly

EXAMPLE 1 (Synthesis of microgels)

(i) The following materials were employed. PEG 6000 (Polyethyleneglycol; the code 6000 represents the approximate molecular weight) wassupplied by BP and was vacuum dried at 90-95° C. for at least 4 hoursusing a Rotavapor (trademark) drier and was stored molten in an oven at80° C. until used. The hydroxyl numbers of the dried PEGs weredetermined by a standard method. The number average molecular weightvalue calculated from these hydroxyl numbers was 5830. Desmodur W(dicyclohexyl methane diisocyanate) was obtained from Bayer and was usedwithout further purification. 1,2,6-hexantriol (HTP) was provided byAldrich and used without further purification.

Caffeine (Aldrich, Mw: 235), bovine serum albumin (BSA) (obtained fromSigma, Mw:66,000) and polyvinyl pyrrolidone (Aldrich, Mw: 10,000) wereused as model drugs for controlled drug delivery.

Methyl ethyl ketone (MEK) was supplied by Aldrich and was dried overanhydrous calcium sulphate (20-40 mesh) and molecular sieve (4A type, 20mesh) for at least 24 hours and distilled fresh before use. Thesolubility parameter of MEK is 18.4 J^(1/2) ml^(-3/2).

Chloroform and petroleum ether (60-80° C. b.p.) were used as supplied byAldrich.

Anhydrous ferric chloride (FeCl₃) supplied by BDH was used as catalyst.

Wheaton glass serum bottles and their corresponding seals withteflon-faced septum were supplied by Aldrich and were used as thereaction container.

(ii) Microgel samples were prepared using the following route. Theinitial reactions were carried out in solvent-free bottles and then thereactants were diluted with solvent after various initial reactiontimes. Molten PEG6000 was weighed in a bottle and there was addedthereto hexantriol in which anhydrous FeCl₃ was dissolved. Theconcentration was monitored so to give a concentration of FeCl₃ in thetotal reactants of 0.2 mg/g. These reactants were mixed together andthen Desmodur W was added. The bottle was placed in an oven at 80° C.and samples were withdrawn at different times, e.g. 5 mins, 10 mins, 15mins, 20 mins and 25 mins. In a second step the samples were diluted inmethyl ethyl ketone to different concentrations, i.e. 5.8, 8.7 and 11.6%(wt./vol.). Additional catalyst was included in the solvent used fordilution, so the total concentration of the catalyst in the solution was0.5 g/100 ml. The solutions sealed in the bottles were put back in thesame oven for further reaction. (The samples withdrawn at 20 mins andmarked with an asterisk were actually macrogeled before dilution, andfall outside the present invention.)

Results are shown in Table 1 where Ti represents the initiallysolvent-free reaction time. The molar ratio is PEG: hexantriol: DesmodurW.

                  TABLE 1                                                         ______________________________________                                        Samples of Solvent-Free Initial Reaction.                                       SAMPLE    Ti(min)  Molar Ratio                                                                            Solvent                                                                              Concentration                            ______________________________________                                        X4-5-3   5       1:4:7      MEK    11.6                                         X4-10-3 10 1:4:7 MEK 11.6                                                     X4-15-3 15 1:4:7 MEK 11.6                                                     X4-20-3 20* 1:4:7 MEK 11.6                                                    X3-5-3  5 1:3:5.5 MEK 11.6                                                    X3-10-3 10 1:3:5.5 MEK 11.6                                                   X3-15-3 15 1:3:5.5 MEK 11.6                                                   X3-20-3 20* 1:3:5.5 MEK 11.6                                                  X2.5-5-3  5 1:2.5:4.75 MEK 11.6                                               X2.5-10-3 10 1:2.5:4.75 MEK 11.6                                              X2.5-15-3 15 1:2.5:4.75 MEK 11.6                                              X2.5-20-3 20* 1:2.5:4.75 MEK 11.6                                             X1.5-5-3  5 1:1.5:3.25 MEK 11.6                                               X1.5-10-3 10 1:1.5:3.25 MEK 11.6                                              X1.5-15-3 15 1:1.5:3.25 MEK 11.6                                              X1.5-20-3 20 1:1.5:3.25 MEK 11.6                                            ______________________________________                                    

The completion of the reaction was indicated by the disappearance of theisocyanate IR peak at 2225 cm⁻¹. The reaction will normally take lessthan 24 hours. All the microgels were insoluble in water and soluble inchloroform.

Samples marked * are for comparison only.

EXAMPLE 2 (Crystallisation)

Microgel granules were prepared by direct filtration of a microgelsolution after leaving the solution in a freezer at -15° C. for 20minutes. The microgel and the solvent were easily separated. Becausethere was still some solvent left in the filtered samples a small amountof petroleum ether (60-80° C.) was used to wash the separated microgelsamples. Washing prevented the flocculation of crystallised granulesfrom sticking together. The samples were then dried in a vacuum ovenovernight. The amount of microgel recovered from the crystallisation waswell above 96% excluding the loss of materials during work-out.

The particle sizes of the microgel granules were measured using aMalvern 2600 model laser scattering particle sizer. Results are shown inTable 2.

FIG. 1 shows the distribution of particle sizes for sample X2.5-5-1.Comparing the results shown in Table 2, the higher the concentration ofmonomers, the bigger the average particle size of the crystallisedgranules. The change of the specific area as the monomer concentrationchanges also reflect the same trend. The particle sizes, on the otherhand, were quite uniform for each sample.

                  TABLE 2                                                         ______________________________________                                                Conc. of Monomer                                                                            Specific Area                                                                             Average Size                                  SAMPLE (g/100 ml) (sq m/cc) (μm)                                         ______________________________________                                        X2.5-5-1                                                                              5.8           0.1422      66.51                                         X2.5-5-2 8.7 0.0987 72.21                                                     X2.5-5-3 11.6 0.0946 73.52                                                  ______________________________________                                    

EXAMPLE 3 (characterisation)

1) Molecular Weight and Molecular Structure

GPC (Gel Permeation Chromatography) was used to measure the molecularweight of the microgel samples. The experiments were carried out usingfollowing conditions:

a) Waters Model 510 pump, 1.0 ml/min, 600-800 psi

b) Knaur Differential Refractometer

c) Waters WISP 710B automatic sample injector, injection volume 100 μl.

d) Waters 745 data module

e) Waters Ultrastyragel-linear and Ultrastyragel-500A columns.

Sample concentration was 0.1 g/100 ml. Sample solutions were filteredbefore injecting into the gel permeation chromatograph using a Watersdisposable 0.54 μm filter. Chloroform was employed as the solvent.

The system was calibrated with polyethylene glycol standards which weresupplied by Polymer Laboratory Ltd.

The molecular weight of the microgels prepared via the "solvent-free"route of the present invention was much higher than that of themicrogels prepared by conventional solution polymerisation. All thesamples had a single peak on a GPC curve which indicated that thecomposition of each microgel sample was uniform. Or in other words, theywere all intramolecularly crosslinked but had different sizes. The totalreaction could be divided into

a) initial stage reaction in the absence of solvent, and

b) further reaction in solution after solvent was added.

Both steps were essential to form such microgels as the first stepreaction (because of the high reactant concentration) should be fasterand effective, so long as the crosslinking was still microscopic, tillsolvent was added.

Macrocelation is probably avoided by steric stabilization provided byPEG chains chemically anchored around the microgel cores.

                  TABLE 3                                                         ______________________________________                                        Molecular Weight                                                                   SAMPLE   Mw           Mn    Mw/Mn                                        ______________________________________                                        X2.5-5-3  169516       92478   1.83                                             X2.5-10-3 115411 42712 2.70                                                   X2.5-15-3 130466 43844 2.97                                                 ______________________________________                                    

2) Glass Transition and Crystallinity

DSC (Differential Scanning calorimetry) experiments were carried on aDuPont Model 910 DSC instrument coupled with a DuPont Model 990 thermalanalyser. Some 3-5 mg of sample was transferred to an aluminium pan. Thepan was then sealed hermetically and heated from the startingtemperature to a limit temperature at a rate of 5° C./min as statedlater. The DSC cell was constantly purged with dry nitrogen gas to avoidmoisture contamination during the operation.

The DSC characterisation results are losted in Table 4. The experimentswere carried out at a heating rate of 5° C./min. Data for PEG6000polyethylene oxide is included for comparison.

                  TABLE 4                                                         ______________________________________                                        DSC Results.                                                                             Tg        Tm    ΔH.sub.f                                                                       PEG                                           SAMPLE (° C.) (° C.) J · g-1 w/w % Crystallinity     ______________________________________                                        X3-5-3 -120.34   51.18   110.7  76.0   66.2                                     X3-10-3 -115.42 46.37 68.22 76.0 40.8                                         X2.5-5-3 -114.53 50.25 99.61 78.7 57.5                                        X1.5-5-3 -106.21 51.48 120.5 84.7 64.6                                        X1.5-5-3 -113.9 48.52 88.70 84.7 47.6                                         X1.5-10-3 -108.93 52.99 105.8 84.7 56.7                                       PEG6000 -94.37 65.68 219.0 100 99.5                                         ______________________________________                                    

The glass transition of the microgel should be determined mainly by thesoft segment of each microgel molecule which was composed of PEG chains;since the quantity of the hard core, i.e. urethane bonds andcrosslinkers, was quite low (the weight percentage of these componentswas normally less than 15%). The structure of each microgel molecule isassumed to comprise a central core having anchored thereto PEG chains orloops.

The degree of the crystallinity of the microgels and the PEG can bemeasured by measuring the heat of fusion which is related to the meltingof crystalline PEG in microgel samples.

    ΔH.sub.f =--BO

m: sample mass in mg

A: area of the curve in cm²

Bo: instrumental constant

ΔH_(f) : heat of fusion in J.g⁻¹

The heat of fusion of 100% crystalline PEO (polyethyleneoxide) was takenas 220.12J.g⁻¹. By dividing the heat of fusion of each microgel by theheat of fusion of the 100% PEO, the degree of the crystallinity in thetotal polymer was obtained. The degree of crystallinity in the PEOfraction of the microgel was further calculated, taking account of theproportion of PEG in each microgel.

EXAMPLE 4 (Controlled Drug Delivery)

1) Tablets made by Direct Compression

FIGS. 2 and 3 show the release of bovine serum albumin (BSA), polyvinylpyrrolidone (PVDP) and caffeine from a tablet. The tablets were made bydirect compression of a mixture of microgel X2.5-3 and each model drug.The loading was 10% (w/w) and the pressure applied was 5 tons. The sizeand the weight of the tablets were: diameter 13 mm and thickness 3 mm,and 0.5 grams respectively. Release experiments were carried out in astandard dissolution apparatus at 37° C. in water. Paddle speed was 60rpm. The release of bovine serum albumin, PVDP and caffeine weremonitored by UV absorption at 280 nm, 215 nm and 274 nm respectively.

The tablets were insoluble in water, and did not disintegrate even atthe end of the release experiment but did swell. A typical swollentablet measured 20 mm diameter×60 mm thickness.

2) Tablets Made by Melting and Compressing

Tablets could also be made by a melting and compressing process. Thus, amixture of the microgel and a drug such as caffeine which is stable atelevated temperature was heated to 80° C. for 20 minutes. The moltenmixture was then compressed to form tablets or balls using a specialmould. The so-prepared tablets swell in water and will normally providea more prolonged release than those prepared by direct compression.Release profiles are shown in FIG. 4.

This method of preparing tablets may form the basis of an economicalhigh-speed production of constant-release swelling devices usingconventional tabletting equipment. This kind of tablet could also beinjection moulded.

It is surprising that the microgel tablets made by either directcompressing or by melting and compressing do not disintegrate whenimmersed in water for a long time. The crystallinity and theintermolecular entanglement of the microgel may play an important rolein this.

Another feature for these tablets is that the rate of release of highmolecular weight substances, i.e. PVDP and BSA, from the microgeltablets is relatively high. Without wishing to be restricted to anyparticular scientific theory, this could be attributed to a differentrelease mechanism. For conventional non-porous hydrogels, diffusion viafree volume governs the rate of the release. Hence substances ofdifferent molecular weights have quite different release rates. Thehigher the molecular weight the slower the release. For microgeltablets, small channels ranging from 1 μm within the tablets have beenseen in electromicrographs. These channels can then provide fasterrelease for the high molecular weight agents than would be obtainedusing non-porous hydrogels.

We claim:
 1. A process for producing a microgel comprising:subjecting,in a first step substantially free of solvent for the essentialreactants required for the formation of the microgel in a cross-linkingpolymerization reaction, at least one monomer to a polymerizationreaction consisting essentially of a cross-linking polymerizationreaction, said at least one monomer being present in a reaction mixtureat a concentration favoring intermolecular cross-linking; andthereafter, dissolving, in a second step initiated before macrogelationcan occur, the reaction mixture with a solvent to a reducedconcentration favoring intramolecular cross-linking, said solvent beingsubstantially non-reactive in said cross-linking polymerizationreaction, and said cross-linking polymerization allowed to proceedfurther, so as to produce a microgel.
 2. A process according to claim 1wherein said microgel is a polyurethane microgel.
 3. A process accordingto claim 1 wherein said at least one monomer is a polyalkylene oxide. 4.A process according to claim 3 wherein said polyalkylene oxide is apolyethylene glycol of number average molecular weight in the range fromabout 3000 to about 10,000.
 5. A process according to claim 3 whereinthe polyalkylene oxide is cross-linked by means of a diisocynate.
 6. Aprocess according to claim 1 wherein there is provided at least onepolyfunctional compound selected from the group consisting of aromaticand aliphatic polyols, for promoting branching to form a branchedpolyurethane.
 7. A process according to claim 6 wherein thepolyfunctional compound is an aliphatic triol.
 8. A process according toclaim 7 wherein there are provided a polyethylene glycol, an aliphatictriol and a diisocynate for reaction in the cross-linking polymerisationreaction.
 9. A process according to claim 8 wherein the molar ratio ofpolyethylene glycol to triol to diisocyanate is 1:1 to 8:2 to
 15. 10. Aprocess according to claim 1 wherein the solvent for said second stephas a solubility for the microgel at ambient temperature, such as toallow the microgel to be precipitated directly from solution without theaddition of any other substance to effect precipitation.
 11. A processaccording to claim 1 wherein there is added an amount of said solventsuch as to dilute said reaction mixture to a reduced concentration offrom 2 to 30% wt/volume.
 12. A process according to claim 1 wherein saidfirst step is carried out for a time period of 1 to 60 minutes.
 13. Aprocess according to claim 12 wherein said time period is from 5 to 30minutes.
 14. A process according to claim 1 wherein said cross-linkingpolymerisation is carried out at a temperature of 50 to 100° C.
 15. Aprocess according to claim 10 wherein precipitation of the microgel isachieved by cooling the reaction mixture to a temperature in the rangeof from 10 to 25° C.
 16. A process according to claim 1 wherein saidcross-linking polymerization is carried out so as to produce a microgelhaving a weight average molecular weight above 40,000.
 17. A processaccording to claim 16 wherein said weight average molecular weight is inthe range from 100,000 to 200,000.
 18. A sustained release devicecomprising a microgel produced by a process according to claim 1 and anactive agent capable of being released from said microgel.
 19. A deviceaccording to claim 18 which device is in the form of a solid body formedof a compress of microgel granules.
 20. A device according to claim 18wherein the active agent is a protein or peptide.
 21. A processaccording to claim 1 further characterised in that no cross-linkingpolymerization reactant is added in said second step.
 22. A processaccording to claim 1 which process is substantially anhydrous.
 23. Aprocess according to claim 11 wherein said reaction mixture is dilutedto a reduced concentration of from 5 to 20% w/v.
 24. A process accordingto claim 10 which includes the further step of precipitating themicrogel out of solution by cooling thereof.
 25. A process according toclaim 24 in which is produced a microgel having a crystalline portion,wherein the reaction mixture is cooled to a temperature below thetemperature at which said cross-linking polymerization reaction iscarried out and below the melting temperature of the crystalline portionof the microgel.
 26. A process according to claim 24 wherein the solventis recovered after precipitation for reuse without further processing.27. A process according to claim 24 which is carried out so as toproduce microgel granules having a granule size of from 0.01 to 5 mm.28. A process according to claim 27 wherein said granule size is from 1to 5 mm.
 29. A device according to claim 18 wherein said active agent isa living microorganism.
 30. A device according to claim 18 wherein saidactive agent is selected from the group consisting of pharmaceuticals,bacteriostats, viricides, insecticides, herbicides, larvicides,fungicides, algicides, nematicides, anthelmintics, topical ordermatological agents, anti-foulants for marine growth prevention,enzymes, preservatives, surfactants, pigments, disinfectants, andsterilizing agents.
 31. A device according to claim 18, wherein saiddevice is in the form of a solid body formed by melting and compressingthe microgel.
 32. A device according to claim 31 wherein the solid bodyis formed by heating the microgel to 80° C. for 20 minutes.
 33. A deviceaccording to claim 31 wherein said solid body is formed by injectionmoulding.